The invention relates to copolymer pharmaceutical compositions useful in oral administration of a number of biological agents.
A variety of biological agents are currently in use for the treatment of diseases and disorders. Many of these agents may be administered topically, rectally, vaginally, by pulmonary route, or parenterally.
However, parenteral administration (such as intramuscular, subcutaneous, intraperitoneal, intra-arterial or intravenous) as well as rectal, vaginal, and pulmonary routes, are often inconvenient, costly, or both. Oral administration thus possesses several advantages over these other routes. It is a convenient, cost-effective mode of administration for the patient.
The present invention relates, among other things, to (1) pharmaceutical compositions and methods for chemotherapeutic agents and (2) pharmaceutical compositions for biological agents, particularly those whose target cells or tissues are resistant to the biological agent.
A number of chemotherapeutic agents exhibit low solubility and stability in physiological fluids. Often, chemotherapeutic agents are poorly transported across cell membranes. Further, many of these agents are binding with plasma proteins as well as other nonspecific interactions in the blood stream before they can reach the target cancer.
Multi-Drug Resistance
A major roadblock to effective chemotherapeutic treatments is the resistance to biological agents that many neoplasms and microbial infections develop. The sensitivity of neoplastic cells to anti-cancer agents can decrease by a factor as high as 103 during the course of a chemotherapeutic regimen. When such resistance develops with respect to one agent, often the target cells are found to also be resistant to a number of other biological agents to which they had not previously been exposed. See Goldstein et al., Crit. Rev. Oncol. Hematol., 12:243-253 (1992); Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 8th Ed., McGraw-Hill, New York, 1994. One mechanism by which such resistance develops is believed to involve the membrane pump protein gp-170 (a glycoprotein P or P-gp protein). See Goldstein et al., Crit. Rev. Oncol. Hematol, 12:243-253 (1992).
It has now been discovered that these difficulties can be overcome by administering the biological agent in question in a formulation containing micelles of one or more block copolymers with the characteristics described below. Further, it has now been discovered that a certain subset of these block copolymers is particularly effective in delivering drugs and reversing resistance to a biological agent.
The Blood Brain Barrier
The brain is isolated from circulatory blood because the endothelial cell lining of blood vessels in the brain is more selective than it is in other parts of the body with respect to the molecules that are allowed to diffuse into the interstitial space of the brain. The mechanism that isolates the brain is often referred to as a xe2x80x9cblood-brain barrier.xe2x80x9d As a result of the blood-brain barrier, biological agents that are intended to affect the brain or a disease in the brain often must be administered in high dosage to compensate for the diffusion barrier provided by the blood-brain barrier. Animals to whom the high doses are administered are at greater risk of experiencing toxic or other side effects. It is therefore desirable to enhance the permeability of chemotherapeutic agents across the blood-brain barrier. See, Goodman""s and Gilman""s The Pharmacological Basis of Therapeutics, Eighth Edition, p. 11.
In the brain and in other tissues it is often desirable to target a biological agent to a particular tissue at which the agent is anticipated to beneficially act. This desirability is particularly true for chemotherapeutic agents that potentially have highly toxic effects on non-target tissues. For instance, most anti-cancer chemotherapeutic agents function by selectively poisoning replicating cells. This mechanism inevitably targets the rapidly replicating cells, such as those of the bone marrow that generate a number of important blood cells. If the biodistribution of the chemotherapeutic drug is changed so that useful concentrations are maintained in the cancerous tissue or the tissue in which the cancer resides while concentrations distal from the cancer situs are reduced, the scope of toxic side effects will generally be reduced.
Additionally, since cancer, antimicrobial and other biological agents exhibit toxicities, it would be beneficial if dosages were lowered without adversely affecting the therapeutic index.
Tumors of the central nervous system present a particularly difficult therapeutic challenge. Such tumors are often difficult to surgically excise and surgical excision can have unacceptable consequences. These tumors can be difficult to treat with radiation since they are sometimes difficult to precisely locate and are often too close to tissues that are critical to the well-being of the tumor patient. Such tumors cannot be effectively treated by standard chemotherapies since the fraction of the administered chemotherapeutic agent that will reach the tumor is very small. The effective dosage at the tumor cannot be increased by administering higher dosages to the patient, since standard dosages are generally close to the dose that cause unacceptable side effects.
Cytokines
Cytokines are polypeptides secreted by cells. Cytokines play an important role in the interactions between cells in the immune system, and are therefore potentially effective drugs for the treatment of cancer, as well as viral-related and other diseases. The mechanism of action of these protein factors is connected with specific activation of the immune system which, in turn, protects against many pathological processes. Well known are antiviral preparations on the-basis of interferons (Infs) that are already used in clinical practice. For example, clinical tests of interleukin-2 (IL-2) and tumor necrosis factor (TNF) as anticancer drugs have yielded promising results. A great deal of work has been devoted to creation of new drugs on the basis of IL-4 and other lymphokines.
Generally speaking, recombinant cytokines possess low affinity for specific receptors on target cells because of incorrectly formed tertiary structures and the absence of necessary post-translational modifications in bacterial super-producers. Such recombinant preparations display low biological activity, and very high doses are required, producing considerable side effects.
Hormones
Hormones are chemical messenger molecules secreted by endocrine glands which regulate various aspects of metabolism. Insulin, for example, is a protein hormone secreted in the pancreas by the islets of Langerhans. Insulin stimulates catabolism of glucose and blocks glycogenolysis, thereby facilitating diffusion of glucose into most cells. The inability to form insulin results in diabetes mellitus, which is currently treated through insulin injection in conjunction with dietary regulation to control blood sugar levels. Insulin production and thus is of particular interest in molecular biology and enzymology.
It is therefore desirable to administer a biological agent or agents to a patient in a composition which can be administered orally, and which alleviates some or all of the above difficulties.
The present invention thus relates to compositions for oral administration comprising a biological agent and a block copolymer.
In one embodiment, the invention provides a pharmaceutical composition comprising:
(a) a biological agent;
(b) a polyether block copolymer comprising an A-type linear polymeric segment joined at one end to a B-type linear polymeric segment, wherein the A-type segment is of relatively hydrophilic character, the repeating units of which have molecular weight contributions between about 30 and about 500, wherein the B-type segment is of relatively hydrophobic character, the repeating units of which have molecular weight contributions between about 30 and about 500, wherein at least about 80% of the linkages joining the repeating units for each of the polymeric segments comprise an ether linkage; and
(c) a targeting moiety coupled to a lipophilic moiety comprising a hydrocarbon having from about 3 to about 41 carbon atoms, more preferably a hydrocarbon having from about 5 to about 25 carbon atoms, and more preferably, a hydrocarbon having from about 9 to about 17 carbon atoms.
The invention thus relates to pharmaceutical compositions comprising a biological agent and a poly(oxyethylene)-poly(oxypropylene) block copolymer. Preferred compositions include those wherein the poly(oxypropylene) [i.e., hydrophobe] portion of said block copolymer comprises at least 50% by weight of the block copolymer. Also preferred are compositions wherein the hydrophobe molecular weight of the block copolymer is at least about 900, and more preferably at least about 1700. Especially preferred are compositions wherein the hydrophobe molecular weight of the polyether block copolymer is at least about 2000 and the hydrophobe weight percentage is at least about 20%. The invention also relates to methods of treatment using the same.
Also preferred are compositions wherein the block copolymers have a critical micellar concentration (xe2x80x9cCMCxe2x80x9d) of about 0.5% wt/vol. or less at 37xc2x0 C. in an isotonic aqueous solution.
In yet another preferred embodiment, the polyether block copolymer is selected from the group consisting of polymers of formulas:
Axe2x80x94Bxe2x80x94Axe2x80x2,xe2x80x83xe2x80x83(I)
Axe2x80x94B,xe2x80x83xe2x80x83(II)
Bxe2x80x94Axe2x80x94Bxe2x80x2,xe2x80x83xe2x80x83(III)
or
L(Rxe2x80x2)(R2)(R3)(R4)xe2x80x83xe2x80x83(IV)
wherein A and Axe2x80x2 are A-type linear polymeric segments, B and Bxe2x80x2 are B-type linear polymeric segments, and R1, R2, R3 and R4 are either block copolymers of formulas (I), (II) or (III) or hydrogen and L is a linking group, with the proviso that no more than two of R1, R2, R3 or R4 is be hydrogen.
In a preferred embodiment, the composition is adapted to include micelles composed of the block copolymer or to form micelles composed of the block copolymers during the course of administration or subsequent thereto. Preferably, at least about 0.1% of the biological agent is incorporated in the micelles, more preferably, at least about 1.0% of the biological agent, yet more preferably, at least about 5% of the biological agent.
In a preferred embodiment, the hydrophobe percentage of the copolymer of the composition is at least about 50% more preferably, at least about 60%, yet more preferably 70%.
In another preferred embodiment, the hydrophobe weight of the copolymer is at least about 900, more preferably, at least about 1700, yet more preferably at least about 2000, still more preferably at least about 2300.
In further preferred embodiments, the hydrophobe weight is at least about 2000 and the hydrophobe percentage is at least about 20%, preferably 35%; or the hydrophobe weight is at least about 2300 and the hydrophobe percentage is at least about 20%, preferably 35%.
In another preferred embodiment, the copolymer or copolymers of the composition have a critical micellar concentration (xe2x80x9cCMCxe2x80x9d) of no more than about 0.5% wt/vol. at 37xc2x0 C. in an isotonic aqueous solution, preferably, no more than about 0.05% wt/vol., more preferably, no more than about 0.01% wt/vol., yet more preferably, no more than about 0.003% wt/vol.
Preferably, the copolymers of the composition conform to Formula (V), which is set forth in the text below. Particularly preferred among these copolymers are those having hydrophobe weights between about 1500 and about 2000, preferably between about 1710 and about 1780, and hydrophobe percentages between about 85% and about 95%, preferably between about 88% and about 92%. Also particularly preferred among these copolymers are those having hydrophobe weights between about 3000 and about 3500, preferably between about 3200 and about 3300, and hydrophobe percentages between about 15% and about 25%, preferably between about 18% and about 22%. Additionally particularly preferred among these polymers are that having hydrophobe weights between about 3500 and about 4000, preferably between about 3700 and about 3800, and hydrophobe percentages between about 25% and about 35%, preferably between about 28% and about 32%.
In a preferred embodiment, the biological agent of the composition is an agent that affects the function of the brain or treats or prevents a disease of the brain.
In a second embodiment, the invention provides a pharmaceutical composition comprising an biological agent solubilized in polymeric micelles having associated therewith a targeting moiety coupled to a lipophilic moiety comprising hydrocarbon having from about 3 to about 41 carbon atoms, more preferably a hydrocarbon having from about 5 to about 25 carbon atoms, yet more preferably, a hydrocarbon having from about 9 to about 17 carbon atoms.
In another embodiment, the invention provides a method of targeting a biological agent to a pre-selected tissue. The method comprises administering the composition described above, be wherein the targeting moiety is selected to target the tissue, to an animal having the pre-selected tissue.
In yet another embodiment, the invention provides a method of treating a microbial disease or a tumor of the brain by administering a composition comprising:
(a) a chemotherapeutic agent; and
(b) a polyether block copolymer comprising an A-type linear polymeric segment joined at one end to a B-type linear polymeric segment, wherein the A-type segment is of relatively hydrophilic character, the repeating units of which contribute an average Hansch-Leo fragmental constant of about 0.4 or less and have molecular weight contributions between about 30 and about 500, wherein the B-type segment is of relatively hydrophobic character, the repeating units of which contribute an average Hansch-Leo fragmental constant of about xe2x88x920.4 or more and have molecular weight contributions between about 30 and about 500, wherein at least about 80% of the linkages joining the repeating units for each of the polymeric segments comprise an ether linkage. In a preferred embodiment, the composition used in this embodiment will include a targeting molecule.
In yet another embodiment, the invention relates to compositions for the delivery of biologically active agents comprising a poly(oxyethylene)-poly(oxypropylene) block copolymer and at least one of (a) a protein, peptide, or derivative thereof, or (b) a biologically active agent, or derivative thereof having reduced cellular transport, reduced penetration into tissues, or reduced penetration across biological barriers, due to membrane proteins, wherein the hydrophobe percentage of the poly(oxyethylene)-poly(oxypropylene) block copolymer is at least about 50%.
The preferred block copolymers are of the formula: 
in which x, y, z, i, and j have values from about 2 to about 800, and wherein for each R1, R2 pair, one is hydrogen and the other is a methyl group.
In another preferred embodiment, the invention relates to compositions for the delivery of a biologically active agent, or derivative thereof, comprising a biologically active agent, or derivative thereof, and a POE-POP block copolymer of the formula: 
wherein for each R1, R2 pair, one is hydrogen and the other is a methyl group.
In yet another preferred embodiment, the invention relates to compositions for the delivery of a biologically active agent, or derivative thereof comprising a biologically active agent, or derivative thereof, and a POE-POP block copolymer of the formula: 
in which x, y, and z have values from about 2 to about 800.
In still another preferred embodiment, the invention relates to compositions comprising at least one block copolymer with ethylene(oxide) content of 50% or less, and at least one block copolymer with ethylene(oxide) content of 50% or more, and a biologically active agent. The ratio by weight of the block copolymer with ethylene(oxide) content of 50% or less to the block copolymer with ethylene(oxide) content of 50% or more is 1:2, more preferrably 1:5.
The protein, peptide or derivative thereof may be preferrably, for example, an immunomodulator, cytokine, hormone, enzyme, tissue plasminogen activator, clotting factor, colony stimulating factor, neuropeptide, recombinant soluble receptor, monoclonal antibody, or erythropoietin. Preferred hormones include human growth hormone, and insulin.
The invention also relates to methods of treating a mammal using these compositions.
The invention also relates to compositions for oral delivery which comprise mixtures of at least one block copolymer with ethylene(oxide) content of less than 50% (i.e., hydrophobic copolymer), and at least one block copolymer with ethylene(oxide) content of more than 50% ((i.e., hydrophilic copolymer). Preferably, these will be in a ratio of 2 hydrophilic copolymers to 1 hydrophobic copolymer, and more preferably in a ratio of 5 hydrophilic copolymers to 1 hydrophobic copolymer, and even more preferably in a ratio of 10 hydrophilic copolymers to 1 hydrophobic copolymer.